This proposal brings together investigators with a long track record in studying epigenetic gene silencing, and associated promoter DNA hypermethylation, in cancer to study the interaction of these events with key environmental exposures which foster cancer risk. The intent is to test, using a unique animal model, the hypothesis that a critical key to how environmental factors increase cancer risk is by modulating and/or inducing heritable epigenetic gene silencing events which allow cells to survive stress and, thus, engage in the early clonal expansion from which cancers arise. To study this, the intent of this initiative is to utilize Hic1 mice which develop gender specific, and age related, epithelial (lung, Gl, liver, etc), soft tissue, and lymphoid tumors based on there being one allele step away from an epigenetic gene silencing event. HIC1 is a gene frequently epigenetically silenced in human cancers. In all cases, the remaining wild type Hid allele, in tumors from the Hic1 mice, is transcriptionally silenced in association with promoter DNA hypermethylation. The gene encodes a transcriptional represser for SIRT1, a key sensor of cell stress, mediator of survival, and regulator of p53. Hid deficient mouse and human tumor cells have increased SIRT1 with resultant diminished p53 function and defective apoptosis response to DNA damage. Intriguingly, SIRT1 is, itself, a chromatin modifying protein which has recently been found to participate in the aberrant silencing of cancer genes. This initiative will thus test how this novel network of epigenetic abnormalities may be induced and/or modulated by important environmental factors, such as dietary folate levels, carcinogen exposure (NNK and PhIP), and inflammatory responses to allow cells to abnormally survive stress and become at risk for cancer. For all tested environmental events, incidence and rates of tumor development in Hic 1 vs. mice will be mapped and matched with the sequence of changes in Hic 1 methylation and expression status, levels of SIRT1, and the methylation and expression status of key cancer genes. These studies should provide, in terms of public health, documentation that the earliest key steps for risk of important cancers may involve heritable, and potentially reversible, epigenetic events. These, in turn, may be driven, and/or modulated, by key environmental factors. Thus, it is inferred that a key to cancer prevention may be to induce reversal of, or block, epigenetic gene silencing.